Attenuated cocaine-seeking after oxytocin administration in male and female rats.

Initial drug abstinence (modeled here as Extinction Day 1, ED1) is a critical time point in the progression of addiction that is strongly influenced by stress and sex. ED1 induces corticosterone release in both sexes, and cocaine-seeking during ED1 can be mitigated by corticotrophin-releasing factor (CRF) antagonists more effectively in female rats. Oxytocin (OXT) is a neuropeptide that has several biological functions, including regulation of stress pathways. To investigate a relationship between OXT, sex, and cocaine-seeking, we examined Fos on ED1 in OXT neurons of paraventricular (PVN) and supraoptic nuclei (SON) compared to homecage (cocaine experienced) or naïve male and female rats. We also administered OXT 30 min prior to ED1 testing or cued reinstatement testing. OXT neurons had decreased activity (as reflected by Fos protein) in PVN and SON on withdrawal day 1 (homecage) compared to naïve rats. Fos in OXT neurons was further decreased on ED1, compared to homecage controls, in both males and females even though in SON, cocaine exposure increased the number of OXT-expressing neurons. In addition, systemically administered OXT reduced cocaine-seeking during ED1 and cue-induced reinstatement of cocaine-seeking but delayed extinction, similarly among male and female rats. These data indicate that OXT neurons in PVN and SON may be involved in cocaine-seeking during ED1 and support OXT as a possible therapeutic to decrease cocaine-seeking during initial abstinence and in response to cocaine-associated cues.